Cancer has become one of the leading causes of death today. The early detection of cancer may lead to desired therapeutic management of cancer and to decrease the mortality rate through effective therapeutic strategies. Advances in materials science have enabled the use of nanoparticles for added contrast in various imaging techniques. More recently there has been much interest in the use of gold nanoparticles as optical contrast agents because of their strong absorption and scattering properties at visible and near-infrared wavelengths. Highly proliferative cancer cells overexpress molecular markers such as epidermal growth factor receptor (EGFR). When specifically targeted gold nanoparticles bind to EGFR they tend to cluster thus leading to an optical red-shift of the plasmon resonances and an increase in absorption in the red region. These changes in optical properties provide the foundation for photoacoustic imaging technique to differentiate cancer cells from surrounding benign cells. In photoacoustic imaging, contrast mechanism is based on the optical absorption properties of the tissue constituents. Studies were performed on tissue phantoms, ex-vivo and in-vivo tumor models to evaluate molecular specific photoacoustic imaging technique. The results indicate that highly sensitive and selective detection of cancer cells can be achieved by utilizing the plasmon resonance coupling effect of EGFR targeted gold nanoparticles and photoacoustic imaging. In conclusion, the combined ultrasound and photoacoustic imaging technique has the ability to image molecular signature of cancer using bioconjugated gold nanoparticles. / text

Optical assays to detect cancer-associated molecular biomarkers in biological substrates are commonly performed with antibody-targeted organic dye contrast agents but the potential for precise quantification, long-term imaging, and multiplexed readouts is limited by chemical and optical instability, non-optimal spectral characteristics, and complicated synthetic chemistry of the dyes. This dissertation tested the hypothesis that a novel class of optical contrast agents termed polymer-protected Raman-encoded nanoparticle tags (PRENTs) provides practical advantages over existing optical technologies for molecular diagnostic applications. First, PRENTs were developed through a modular design utilizing gold-nanoparticle-Raman reporter complexes protected and functionalized by polyethylene glycol derivatives. PRENTs produced optical readouts through surface enhanced Raman scattering (SERS) that were brighter and more photostable than the fluorescence of semiconductor quantum dots under identical experimental conditions. Unique spectral signatures were produced with a broader class of Raman reporters than is possible with silica coated Raman tags. Spectral signatures and colloidal stability of PRENTs were unaffected by harsh chemical conditions that cause spectral changes and aggregation of dyes, quantum dots, and protein coated Raman tags. Antibody-targeted PRENTs specifically tagged cell surface cancer biomarkers on living cells at reasonable integration times. PRENTs were non-toxic to cells under conditions exceeding those required for sensitive molecular detection. Next, PRENTs were efficiently optimized for excitation with near-infrared light through inclusion of near-infrared chromophores as Raman reporters and exploitation of the size-dependent optical enhancement of gold nanoparticles. Third, the development of a slide-based Raman-linked immunosorbent assay using antibody-conjugated PRENTs enabled quantification of protein biomarkers with a dynamic range of 3 to 4 logs. In summary, this dissertation establishes PRENTs as novel optical tags with unique features useful for biomedical applications and provides insights for further assay development.

Cette thèse décrit une stratégie de synthèse de nouvelles générations des nanoparticules (NPs) pour applications biomédicales, visant à une amélioration de leurs performances pour l’imagerie, le diagnostic thérapeutique. Ces NPs présentent plusieurs fonctionnalités leur permettant de réaliser des tâches multiples. Deux types de sondes bimodales ont été développés et étudiés afin d'évaluer leur potentiel comme agents (1) de contraste en IRM et (2) luminescents. Ces objetscombinent les propriétés des complexes de lanthanide (Ln3+) et celles des NPs de silice ou de type coeur-écorce Fe2O3@SiO2 pour une imagerie bimodale. Ces NPs testées sur des cellules vivantes ont permis d’illustrer la preuve du concept aussi bien en IRM avec une augmentation d'intensité des images et un impact significatif sur les relaxivities r1, r2 et r2* qu’en photoluminescence. L’étude du système coeur-écorce a montré que l’influence du contrôle fin de l’écorce autour du noyau d'oxyde de fer a pu être modélisée. / This thesis describes a strategy of synthesis of new generations of nanoparticles (NPs) for biomedical applications, aiming at an improvement of their performances for the imaging, and the therapeutic diagnosis. These NPs present several functionalities enabling them to carry out multiple tasks. Two types of bimodal probes were developed and studied so as to evaluate their potential as contrast agents (1) in MRI and (2) and luminescence. These objects combine the properties of the lanthanide complexes (Ln3+) and those of NPs of silica or core/shell Fe2O3@SiO2 for a bimodal imaging. These NPs tested on living cells were able to illustrate the proof of the concept not only in MRI with an increase of intensity of the images and a significant impact on the relaxivities r1, r 2 and r2* but also in photoluminescence. The study of the core/shell system showed that the influence of the fine control of the shell around the iron oxide core could be modeled.